CHICAGO — Periprocedural anticoagulation with bivalirudin (Angiomax) for a radial-first approach to primary percutaneous coronary intervention (PCI) improved mortality and bleeding risk compared with heparin in the BRIGHT-4 randomized trial from China.
Bivalirudin started with a pre-procedure bolus and carried through to a high-dose infusion for 2-4 hours afterward reduced the composite of all-cause mortality and major Bleeding Academic Research Consortium (BARC) type 3-5 bleeding by a relative 31% compared with heparin monotherapy at 30 days (4.39% vs 3.06%; HR 0.69, 95% CI 0.53-0.91, P=0.0070).
Both mortality and bleeding components also significantly favored the direct thrombin inhibitor in the trial’s 6,016 ST-segment myocardial infarction (STEMI) patients, reported Gregg Stone, MD, of Icahn School of Medicine at Mount Sinai in New York City.
“Bivalirudin could be considered a preferred regimen in the cath lab in patients with STEMI undergoing primary PCI to reduce mortality and overall adverse outcomes,” Stone concluded in presenting the results at a late-breaking clinical trial session at the American Heart Association annual meeting in Chicago. The findings were also published in The Lancet.
“It is difficult to justify withholding a treatment which reduces all-cause mortality,” said Philippe Gabriel Steg, MD, of Hôpital Bichat in Paris, as study discussant at the session, calling it “a clear, unambiguous win for bivalirudin at 30 days.”
“However, we know bivalirudin remains slightly more complex and slightly more expensive than heparin, and it can be difficult to change practice even with good data,” he acknowledged, concluding: “It will also be important to have longer-term follow-up and cost-effectiveness analyses to inform both guideline committees and clinical practice.”
An accompanying Lancet commentary agreed. “[T]he results of BRIGHT-4 might not be strong enough to change future guideline recommendations,” argued J.J. Coughlan, MB BCh, and Adnan Kastrati, MD, both of Deutsches Herzzentrum München in Germany.
In addition to the trial’s open-label design, they noted, the fact that both it and the prior BRIGHT trial supporting bivalirudin given as a bolus plus full-dose post-PCI infusion were conducted in China raises concern that the findings might not be generalizable to non-east Asian populations.
But “at the very least, these findings set the stage for further randomised trials that mandate the use of a full dose post PCI bivalirudin infusion in order to determine whether bivalirudin should become the first choice anticoagulant during primary PCI in all patients with STEMI worldwide,” Coughlan and Kastrati wrote.
Stone’s group, though, suggested the results should be generalizable: “In this regard, although east Asian patients have differences in genetic polymorphisms affecting their response to antiplatelet agents compared with populations from the USA, UK, and Europe, we are not aware of genetic, social, or other differences between populations that should affect the relative outcomes of anticoagulant agents.”
Steg also pointed to the results being in line with an individual patient-data meta-analysis of prior bivalirudin trials in STEMI presented earlier in the day at the conference.
Stone’s group noted that the trial compared the two most preferred anticoagulation regimens in clinical practice for patients with STEMI undergoing PCI, although never before directly compared in an adequately powered randomized controlled trial.
The Bivalirudin With Prolonged Full-Dose Infusion During Primary PCI Versus Heparin Trial (BRIGHT)-4 trial included 6,016 patients getting primary PCI for STEMI at 87 clinical centers in China. They were randomly assigned to receive bivalirudin (given as a 0.75 mg/kg bolus then full-dose infusion at 1.75 mg/kg/h during the PCI procedure and for 2-4 h afterwards) or unfractionated heparin (70 U/kg bolus).
Additional study drug was given in both groups based on activated clotting time less than 225 s 5 minutes after the bolus. Glycoprotein IIb/IIIa inhibition with tirofiban (Aggrastat) could be given only for thrombotic complications during PCI. All patients got aspirin plus clopidogrel or ticagrelor (Brilinta) for prevention after the procedure. Radial artery access — the preferred route for vascular access in the protocol — was used in 93.1% of cases.
Patients averaged 60.5 years of age, and 21.5% were female.
Bivalirudin reduced 30-day all-cause mortality compared with heparin by a relative 25% (2.96% vs 3.92%; HR 0.75, 95% CI 0.57-0.99, P=0.0420) and BARC types 3-5 bleeding by a relative 79% (0.17% vs 0.80%; HR 0.21, 95% CI 0.08-0.54, P=0.0014).
Among the secondary endpoints, 30-day major adverse cardiac or cerebral events was similar between groups as were 30-day rates of reinfarction, stroke, or ischemia-driven target vessel revascularization.
However, there were fewer cases of stent thrombosis within 30 days with the direct thrombin inhibitor (0.37% vs 1.10%, P=0.0015) and a favorable rate of net adverse clinical events, which combined major adverse cardiac or cerebral events and BARC types 3-5 bleeding (4.15% vs 5.55%, P=0.0124).
“Reassuringly, despite the reduction in bleeding observed with bivalirudin, there did not appear to be any increased risk of ischaemic events,” the commentators wrote. “The benefit associated with bivalirudin in this study is even more notable given the use of radial access in almost all patients and the relatively low incidence of bleeding compared with other trials.”
The trial was funded by the Chinese Society of Cardiology Foundation and a research grant from Jiangsu Hengrui Pharmaceuticals.
Stone disclosed financial relationships with Abiomed, Ablative Solutions, Adona Medical, Amgen, Ancora, Apollo Therapeutics, Cardiomech, CorFlow, Elucid Bio, Gore, HeartFlow, Impulse Dynamics, Infraredx, Medtronic, Millenia Biopharma, Miracor, Neovasc, Occlutech, Pulnovo, Robocath, TherOx, Valfix, and Vectorious; and holding equity and options from Ancora, Applied Therapeutics, Aria, Biostar family of funds, Cagent, Cardiac Success, Orchestra Biomed, SpectraWave, Valfix, and Xenter. His daughter is an employee at IQVIA. His employer receives research support from Abbott, Abiomed, Biosense-Webster, Bioventrix, Cardiovascular Systems, Phillips, Pulnovo, Shockwave, Vascular Dynamics, and V-wave.
Steg disclosed being primary investigator of the EUROMAX trial and a speaker/consultant for The Medicines Company more than 5 years ago.